A. The Advantages of Xylitol
The most commonly used sweetener for food and pharmaceutical contexts is sucrose. Sucrose is used for its well-known sweetening properties and also for bulking purposes. Although a wide variety of alternate sweeteners are available, sucrose is generally considered to be the optimum sweetener with regard to taste profile and technological properties. However, sucrose has been implicated as a contributory factor in many diseases including hypertension, coronary heart disease, arterial sclerosis and dental caries. These health concerns have led health care professionals to analyze the effects of sucrose and its prominent role in the diet.
Perhaps the most significant, well-documented effect of sucrose is its contribution to tooth decay. The mouth contains a number of bacterial strains which ferment common dietary carbohydrates such as sucrose. This fermentation generates acid as an end product which lowers the pH in the mouth; the lowered pH leads to a demineralization of tooth enamel and finally to the formation of dental lesions or caries.
It is well known that it is not the total quantity of sugar consumed per se, but the frequency of consumption that contributes to dental caries. Thus, the presence of sucrose and other fermentable carbohydrates in regular meals is not the principal cause of tooth decay. The consumption of fermentable carbohydrates between meals in the form of confections and sweetened pharmaceuticals (and the frequency of such consumption) have been shown to have a close relationship to the formation of dental caries. Long after the candy or drug has been consumed, the fermentable carbohydrate stays in the mouth and is fermented by Streptococcus mutans and other cariogenic bacteria, lowering the mouth pH and promoting dental caries as described above.
One approach to fighting dental caries is to reduce or eliminate the amount of fermentable carbohydrates such as sucrose in pharmaceutical or food contexts. The replacement of fermentable carbohydrates by sugar substitutes which cannot be fermented, or are less easily fermented by S. mutans and other bacteria has been shown to decrease the development of dental caries.
Xylitol has been used as a sugar substitute in certain contexts (e.g. chewing gum: U.S. Pat. No. 4,514,422 (Yang) and U.S. Pat. No. 3,422,184 (Patel)) with practical and commercial success. The use of xylitol is attractive because of its taste and technological advantages. Xylitol is a naturally occurring five carbon sugar alcohol which has the same sweetness as sugar and a caloric content which is less than that of sugar. Xylitol is found in small amounts in many fruits and vegetables and is produced in the human body during normal metabolism. Xylitol is particularly attractive because of its known metabolic, dental and technical characteristics.
From a metabolic perspective, xylitol is metabolized largely independent of insulin, so it can be safely consumed by non-insulin dependent diabetics. Further, xylitol has been shown to delay gastric emptying and to possibly suppress food intake which means it may have an important role in weight reducing diets.
A significant advantage of xylitol is that it is not fermented by S. mutans and other bacteria found in the mouth and, therefore, does not produce acids which, as described herein, contribute to the formation of dental caries. Xylitol is well established as a non-cariogenic substance, i.e. xylitol does not contribute to caries formation. Significant data also exists which supports the view that xylitol is not only non-cariogenic, but actively suppresses the formation of new caries and may even reverse existing lesions by inducing remineralization, i.e. it is a cariostatic material. A summary of clinical data regarding the effects of xylitol and its possible mechanisms is set forth in Bar, Albert, Caries Prevention With Xylitol: A Review of the Scientific Evidence, 55 Wld. Rev. Nutr. Diet. 183-209 (1983). The mechanism or mechanisms by which xylitol effects any cariostatic properties is not yet known, but some possible mechanisms which have been suggested include a reduction of oral levels of S. mutans, a reduction in the development of plaque, the stimulation of the flow of protective saliva, the favorable alteration of the composition of saliva, the retardation of demineralization and an enhancement of remineralization of tooth enamel.
Xylitol also has significant technological advantages, particularly with respect to taste profile. Xylitol produces a pleasant cooling effect in the mouth when consumed in the crystalline state. The energy required to dissolve one gram of xylitol is 34.6 calories, the highest known value for sugars and sugar alcohols; this produces a physical cooling effect which is desirable in many contexts. Xylitol is as sweet as sugar and does not typically manifest unpleasant aftertastes.
Other polyols, such as sorbitol, mannitol, lactitol and others have also been substituted for sucrose in a variety of contexts. All of these polyols have certain advantages--such as non-cariogenicity--over sucrose. However, none of the other polyols have been demonstrated to have a cariostatic effect.
One context in which xylitol has been heretofore utilized with only limited success is as a constituent in tablets. In pharmaceutical contexts, tablets are used for bringing active substances into a size, shape and texture that can be dosaged, chewed, sucked, swallowed whole or dissolved in water for drinking. In food contexts, tablets can take the form of compressed, fruit or mint flavored confections which consist of a sweetener(s), flavor(s) and optionally color and acid. Because of its taste and cariostatic properties as described above, xylitol is a potentially attractive constituent in tablets for both food and pharmaceutical purposes. Xylitol has not been extensively utilized as a binding or diluting agent in this context.
Sweetness in pharmaceutical tablets fulfills the purpose of making the product more pleasant to eat and to mask any unpleasant taste of the active ingredient(s). Today, many pharmaceutical tablets are sweetened with sucrose, lactose and other fermentable carbohydrates which are also used as diluents. Replacing sucrose and other fermentable carbohydrates with xylitol in those applications which must be sweetened would eliminate the use of cariogenic formulations in medicaments such as throat lozenges, cough tablets, vitamins, chewable tablets and others, and also takes advantage of the other attributes of xylitol discussed above, such as its noted cooling effect and metabolic characteristics.
In food contexts, tablets are usually sucked or chewed by the user and are often used as breath mints. Sucrose is the sweetener of choice in these contexts and has bulking properties as well. Replacing sucrose with xylitol would enable tablets to exploit the unique advantages of xylitol, particularly its anti-caries properties, and its pronounced cooling effect.
The cariostatic effect of xylitol is particularly important because clinical studies have shown that it is not the quantity of sucrose (or other acid producing substances such as maltose, lactose and dextrose), but the frequency of sucrose intake that is critical for caries development. Many pharmaceutical and food tablets are designed to be and are consumed at frequent and/or regular intervals throughout the day. For this reason, some dental researchers have suggested switching from sucrose, maltose, lactose, dextrose to a non-acid producing sweetener such as xylitol in pharmaceutical and food contexts.
B. Tableting Techniques and Tablets
Tablets can be formed by compression or by molding.
Modern compression tableting techniques--irrespective of the type (and ultimate shape of the end product)--utilize a piston like device with three stages in each cycle: (1) filling--adding the constituents of the tablet to the compression chamber; (2) compression--forming the tablet; and (3) ejection--removing the tablet. The cycle is then repeated. A representative tablet press is a MANESTY Novapress, manufactured by Manesty Machines Ltd., Liverpool, England, and many others are available.
Because many materials have some, or none, of the required qualities of "flowability" and "compressibility", binding and diluting agents have been developed to permit direct compression to take place. An ideal binding and diluting agent also functions in the tablet either as an active ingredient or as an agent which contributes or improves flavor or other properties. In this context, free flowing means that the particles to be compressed must enter the compression chamber as discreet particles; compressible means the particles form a tablet after compression and do not remain in a powdered or substantially powdered form.
Two critical criteria in the quality of a tablet are crushing strength (or hardness) and friability. The resistance of the tablet to chipping, abrasion, or breakage under conditions of storage, transportation and handling before usage depends on its hardness. Hardness is measured by determining lateral breaking strength (expressed in kilo ponds ("Kp"), Strong Cobb Units wherein 1 kp=1.4 S.C.U.) or Newtons ("N") wherein 10 S.C.U.=70N exerted on a single tablet at the moment of rupture. A representative hardness tester is the Model HT-300 manufactured by Key International, Inc. Acceptable hardness depends on the desired mouthfeel and the expected end use and packaging conditions of the tablet, but in most contexts, tablet hardness must be greater than about 10 S.C.U. to be commercially useful.
Friability is also a standard test known to one skilled in the art. Friability is measured under standardized conditions by weighing out a certain number of tablets (generally 20 or more), placing them in a rotating plexiglass drum in which they are lifted during replicate revolutions by a radial louver, and then dropped through the diameter of the drum. After replicate revolutions, the tablets are reweighed and the percentage of powder "rubbed off" or broken pieces is calculated. Friability in the range of about 0% to 3% is considered acceptable for most drug and food tablet contexts. Friability which approaches 0% is particularly preferred.
Tablets of insufficient hardness exhibit capping and/or lamination and can easily break apart or disintegrate under normal handling and packaging conditions. Tablets of insufficient hardness cannot be used for lozenges or mints which are designed to be sucked in the mouth, releasing the active ingredient(s) or flavor over time, and may have an undesirable powdery, grainy or coarse mouthfeel.
Sweet carbohydrates such as sugars and sugar alcohols are well suited for use as binding and diluting agents, particularly because they can function as an active ingredient or as a flavor improving agent. However, crystalline or powdered sugars and sugar alcohols as such are poorly suited for direct compression techniques because they have poor flowability and/or compressibility. Therefore, granulated sugars or sugar alcohols have been developed for use in direct compression. In pharmaceutical and food industries, granulated forms can be regarded as semi-finished products which are utilized as raw materials in effective tableting techniques.
The prior art discloses binding and diluting agents which contain sugars. For example, commercial binding and diluting agents include an agglomerated dextrose product sold under the trademark EMDEX, an agglomerated sucrose product containing dextrines sold under the trademark DIPAC and a pregelatinized directly compressible starch and mannitol product sold under the trademark STARCH 1500. Finnish Patent Application No. 854,885 discloses a fructose-based binding and diluting agent namely, a fructose agglomerate, suited for use in direct compression tableting techniques. U.S. Pat. No. 4,352,821 to Doran et al. discloses a binding and diluting agent consisting of fructose and a water insoluble carrier consisting of an edible, inorganic salt. U.S. Pat. No. 4,159,345 to Takeo et al. discloses an excipient consisting essentially of microcrystalline cellulose having certain characteristics.
C. Use of Xylitol in Tablet Contexts
Xylitol is not considered to be directly compressible, i.e. crystalline xylitol cannot be compressed into tablets of sufficient hardness and low friability. Therefore, in order to utilize xylitol in tablets, a variety of approaches to impart these characteristics have been used, without complete success.
One method has been to compress xylitol into tablets of relatively low initial hardness (e.g. about 6 S.C.U.) and "finish" the outer surface. The finishing step takes advantage of the unique crystallization properties of xylitol and its low melting point. Basically, the compressed tablets--which have a low initial hardness--are heated by exposing the surface of the tablets to hot air at temperatures greater than 94.degree. C. which cause a phase change in the xylitol from solid to liquid. After cooling, recrystallization occurs quickly and a "glass" hard surface layer is formed. This finishing step, however, adds another significant step to the production process (thereby increasing the cost and decreasing the efficiency), cannot be used in all tablet contexts, and does not result in a tablet with uniform hardness.
Tablets can be formed with xylitol by means of the conventional wet granulation process with gelatin or starch as an additive. Xylitol has also been admixed with other polyols to form a mixture which is then compressed. U.K. Patent No. 1,526,020 to Lifesavers, Inc. discloses a process for the preparation of a tablet containing xylitol utilizing direct compression techniques. In the examples of the patent specification (which disclose the use of xylitol in combination with at least one other polyol), the ratio of xylitol/sorbitol is 1:1 to about 0.43:1 (256:297), and the ratio of xylitol/mannitol is also 1:1. As a consequence, the examples enable only a partial utilization of the anti-cariogenic affect, and advantageous flavoring properties of xylitol, because a major portion of the tablet consists of sorbitol which does not show xylitol's taste and anti-cariogenic qualities.
From a technical perspective, the use of crystalline xylitol produces tablets which are too coarse in many contexts which give rise to a gritty texture and undesirable mouthfeel. The use of milled xylitol (less than 200 micron average particle size) produces a dry blended product (with sorbitol, for example) wherein flowability of the blend is extremely poor (near zero). Tableting machinery equipped with a force feeder is required. Dry blended xylitol and sorbitol is not an acceptable commercial alternative.
The present invention, however, discloses a free flowing, compressible granulate which comprises at least 94% to 98% by weight of xylitol in combination with another physiologically accepted polyol, preferably sorbitol. Sorbitol does not diminish the cooling effect of xylitol (as other constituents may) and also acts as a lubricant in the direct compression context. The granulate is suitable for use as a binding or diluting agent in direct compression techniques. The present invention also contemplates a method for producing such a xylitol-based granulate.